Ziprasidone is an antipsychotic agent that is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents. Ziprasidone has the following structure:

The preparation of ziprasidone base is disclosed in U.S. Pat. No. 4,831,031 (example 16). Preparation of ziprasidone base is also disclosed in U.S. Pat. No. 5,312,925. A process for preparation of ziprasidone HCl monohydrate having a mean particle size equal to or less than about 85 microns is also disclosed in U.S. Pat. No. 6,150,366 and EP 0 965 343 A2.
Ziprasidone has been marketed under the name GEODON as an oral capsule and as an injectable drug. GEODON capsules contain the monohydrate hydrochloride salt of ziprasidone, and come in 20, 40, 60 and 80 mg dosage forms. GEODON for injection contains a lyophilized form of ziprasidone mesylate trihydrate, and contains 20 mg base equivalent of ziprasidone. The mesylate salts of ziprasidone, including monohydrate and trihydrate, are disclosed in U.S. Pat. Nos. 6,110,918 and 5,245,765.
The present invention relates to the solid state physical properties of ziprasidone HCl. These properties can be influenced by controlling the conditions under which ziprasidone HCl is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
Ziprasidone HCl has very low solubility in water (0.08 mg/ml). Increase in specific surface area (SSA) of low aqueous solubility materials may improve therapeutic activity (J. Phys. D: Appl. Phys. 26 (14 Aug. 1993) B181-B187). The surface area of a solid material provides information about the void spaces on the surfaces of individual particles or aggregates of particles (E L Parrott, in Pharmaceutical Technology: Fundamental Pharmaceutics, Burgess, Minneapolis, Minn., 1970, pp 1-36). Factors such as chemical activity, adsorption, dissolution, and bioavailability of the drug may depend on the surface of the solid (E L Parrott, in Pharmaceutical Technology: Fundamental Pharmaceutics, Burgess, Minneapolis, Minn., 1970, pp 1-36, E L Parrott, Pharm. Manuf., 2, 30-37 (1985)). The adsorption of inert gases onto solid materials represents the most widely used method for the determination of SSA, although other methods are available (S L Lowell and J E Shields, Powder Surface Area and Porosity, Chapman and Hall New York, 1984). The BET method (S. Brunauer, P H Emmett and E Teller, J. Am. Chem. Soc., 60, 309 (1938)) is generally used for gas adsorption surface area measurement.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. These conformational and orientational factors in turn result in particular intramolecular interactions and intermolecular interactions with adjacent molecules that influence the macroscopic properties of the bulk compound. A particular polymorphic form may give rise to distinct spectroscopic properties that may be detectable by powder X-ray diffraction, solid state 13C NMR spectrometry and infrared spectrometry. The polymorphic form may also give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others.
Ziprasidone HCl hemihydrate is disclosed in U.S. Pat. No. 4,831,031, Example 16 (column 13, line 13). A crystalline form of ziprasidone HCl (herein designated Form M) is disclosed in U.S. Pat. No. 5,312,925 and EP 0 586 181 A1. Form M is characterized by XRD, IR and water content. It is reported that the water content of Form M ranges from 3.8 to 4.5% by weight, and that it is a monohydrate. Ziprasidone HCl Form M is prepared from ziprasidone base anhydrous.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. There is a need in the art for additional polymorphic forms of ziprasidone HCl.